Neoadjuvant treatments are the mainstay in the care of patients with breast, colon, and other cancers, but have not traditionally been used in melanoma. This has changed now, with the publication of a report showing that patients with resectable stage III or IV BRAF-mutant melanoma benefit from treatment with the BRAF/MEK inhibitor drugs dabrafenib and trametinib prior to (and continued after) surgery. The randomized clinical trial that produced these findings was small, but the benefits were so obvious that the researchers had to close the control group—those patients who received a placebo instead of neoadjuvant treatment. 71% of the 14 patients in the trial who received BRAF/MEK inhibitors prior to surgery were disease-free after 18 months, whereas all seven patients in the control group experienced a recurrence. The trial is continuing without the control group: all patients will receive treatment prior to surgery

Melanoma patients whose tumors are surgically removed experience a very high rate of recurrence. Until recently, adjuvant treatments to prevent recurrences were limited to the drug interferon alpha-2B and, more recently, ipilimumab (brand name Yervoy), an anti-CTLA-4 immune checkpoint drug approved by the U.S. Food and Drug Administration (FAD) for adjuvant treatment in 2015. Interferon treatment is extremely harsh, with many adverse effects, and is not often used anymore. Yervoy is often associated with autoimmune side effects, which are sometimes quite serious.

Enter nivolumab (Opdivo) the anti-PD-1 checkpoint drug approved by the FDA to treat metastatic melanoma and other cancers. A clinical trial showed that the recurrence-free survival (RFS) rate at 18 months with nivolumab was 66.4% compared to 52.7% for ipilimumab (Yervoy) in patients with resected stage IIIB/C or IV melanoma. This amounts to a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor. Not the least important factor is the much lower rate of side effects seen with nivolumab compared to ipilimumab. Nivolumab is now approved by the FDA as an adjuvant treatment after surgical resection of melanoma.

Pembrolizumab, a competing anti-PD-1 drug, also showed encouraging results in a randomized trial for stage III melanoma. The stakes in this trial were lower, since the control arm received a placebo (not ipilimumab!). Risk reduction was 43%, according to preliminary results of the trial.

For patients with BRAF-mutant stage III melanoma, adjuvant treatment with the BRAF/MEK inhibitors dabrafenib and trametinib was just recently granted a priority review by the FDA, signaling a likely approval soon. Recurrence-free 3-year survival was 58% for the combination versus 39% for placebo.

New treatments for metastatic melanoma

A Knowledge Blog post from last summer described new combination treatments for metastatic melanoma. There have been significant developments since then.

Several trials combined PD-1 blockers (pembrolizumab or nivolumab) with small molecules known as IDO inhibitors. The latter help shut down the activity of immune system cells known as regulatory T cells (T regs), which dampen the immune response triggered by anti-PD-1 drugs. Combination of pembrolizumab with the IDO inhibitor epacadostat increased the rate of responses to pembrolizumab from 32% to 56%. This is very comparable to the response rate seen with the FDA-approved combination of nivolumab and ipilimumab. However, the significant toxicities seen with addition of ipilimumab are not observed when IDO inhibitors are added. Several other competing IDO inhibitors are currently in trials with both pembrolizumab and nivolumab. Importantly, there is also hope that these drug combinations may abolish resistance to PD-1 blockers in previously treated melanoma patients.

Another promising combination has been tested in a small clinical trial of nivolumab with NKTR-214, a specifically modified form of the protein IL-2, which is a strong activator of the immune system. High-dose IL-2 is a drug that has long been approved for metastatic melanoma but is rarely used because of the extremely serious adverse effects. NKTR-214 is a modified (PEGylated) IL-2 that has much reduced side effects, and does not activate inhibitory T regs. Clinical trial results have been released for 11 melanoma patients treated with the combination. Of the patients enrolled, 73% have experienced objective responses, which is obviously much higher than what is seen with nivolumab alone. This trial is now enrolling patients who have or have not already been treated with immune drugs.

Patients who were treated with anti-PD-1 drugs and experience progression may consider enrolling in trials that add relatlimab (an anti-LAG3 immune drug) to nivolumab. In a trial that enrolled heavily pretreated patients who failed on previous treatment with anti-PD-1 drugs, the rate of response was 11.5%, but many more patients (38%) have achieved stable disease. The presence of LAG3 protein (but not PD-L1 protein) in the tumors was predictive of response.

There are other new drugs to watch. TLR9 agonists (activators) have shown early promising results in melanoma. TLR is a group of receptors that are strongly involved in innate immunity. A recent publication showed that intratumoral injection of a TLR9 activator with an antibody to OX40 (a protein on T cells) has extraordinary activity in a mouse cancer model. Trials that combine anti-OX40 and TLR9 agonists are forthcoming. However, two TLR9 agonists, SD-101 and IMO-2125, have shown very promising results in combination with anti-PD-1 or anti-CTLA4 drugs.

The other drug with early promise is ImmunoPulse IL-12 (pIL-12). In combination with pembrolizumab, it induced responses in 43% of patients who had not been previously treated with immune drugs. The important point is that patients in this trial were specifically selected to have a tumor profile that is associated with lack of response to pembrolizumab. pIL-12 is injected into tumors, so this intervention is appropriate for patients who have injectable tumors.

New BRAF/MEK inhibitors for melanoma have emerged: encorafenib and binimetinib produced a 3-year overall survival rate that is twice as high as seen with vemurafenib, a BRAF inhibitor. The comparison is not exactly meaningful because vemurafenib is not used as a single drug in BRAF-mutant melanoma these days, but this phase III trial was initiated back in 2013, prior to the approval of other BRAF/MEK combinations. The new combination may be approved mid-2018.

The triplet combinations for BRAF-mutant melanoma should be mentioned (immune plus targeted drugs). A trial that combined dabrafenib and trametinib with pembrolizumab reported early success, with a confirmed response rate of 67% in 15 patients who received the combination.

“Although modern immunotherapy has yet to have a breakthrough in prostate cancer to the degree it has had in lung cancer or urothelial carcinoma, combinations with anti–PD-1/PD-L1 agents are beginning to show promise for these patients in clinical trials.

“Currently ongoing is a phase II trial of durvalumab (Imfinzi) in combination with the PARP inhibitor olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC; NCT02484404). Investigators note that previous data have suggested that 25% to 30% of sporadic mCRPC has DNA-repair pathway defects. Results thus far have demonstrated that the synergy of durvalumab and olaparib proves that the combination may be a viable option for patients with mCRPC who are heavily pretreated. The trial is still accruing.”

The human gut contains hundreds of species bacteria, which are known to contribute to various bodily functions (such as digestion, of course!) but they also shape our immune system. Now, recent research has revealed how our microbiomes (the abundant bacteria living in our bodies) may affect the efficacy of immune checkpoint blockade (ICB) in cancer treatment.

How it started: about two years ago, an American group of scientists led by Thomas Gajewski of the University of Chicago noticed that melanoma (and some other cancers’) growth in mice was influenced heavily by the type of bacteria found in the mouse gut. They worked with mice purchased from two different vendors, and realized that mice from one vendor had consistently slower-growing tumors. Bifidobacterium bacteria present in the mouse gut were pinpointed to be the culprit, because transfer of Bifidobacterium to mice that did not have it was able to slow down melanoma growth. Treatment with an immune anti-PD-L1 drug was effective in mice that had the bacteria, but not in mice lacking it. Continue reading…

“The addition of atezolizumab to first-line treatment with bevacizumab and chemotherapy significantly prolonged PFS among individuals with advanced nonsquamous non-small cell lung cancer, according to the agent’s manufacturer.

“The randomized, multicenter, open-label phase 3 IMpower150 study assessed the efficacy and safety of atezolizumab in combination of chemotherapy with or without bevacizumab (Avastin, Genentech) for patients with stage IV nonsquamous NSCLC who had not undergone chemotherapy for their advanced disease.”

Non-metastatic breast cancers are most often treated with surgery, but if the tumors are fairly large, or involve nearby lymph nodes, neoadjuvant (pre-operative) treatments with chemotherapy (NAC) are done first. NAC often reduces the tumor size and kills cancer cells in lymph nodes, if present, prior to surgery, improving the outcome. The best possible result of neoadjuvant treatment is pCR (pathologic compete response), when the tumor is no longer visible in imaging studies. Here, I review the new directions in which neoadjuvant treatments are evolving.

Today, treatments for metastatic breast cancers are tailored for specific subtypes. Starting with the introduction of the drug trastuzumab (Herceptin) for HER2-positive cancers, new, more specific treatment options were eventually developed and approved for other types as well. Estrogen deprivation endocrine therapies, lately prescribed in combination with CDK4/6 inhibitors, are used in estrogen receptor (ER)-positive cancers. Triple negative cancers (TNBC) are still treated mostly with chemotherapy, but immune checkpoint drugs and PARP inhibitors are explored in clinical trials, with some successes reported.

However, neoadjuvant treatments (except for HER2+ cancers) remain largely limited to chemotherapy regimens. This is starting to change now, with new approaches tailored to the cancer type being investigated in clinical trials.

In this regard, it is important to mention the I-SPY2 trial, NCT01042379, which started in 2010 and is for women with stage II-III breast cancer. It offers about a dozen drugs that are chosen based on particular features of the newly diagnosed cancers. This trial has a unique design and has produced some important results. Additional treatments and trials for various types of breast cancer are discussed below. Continue reading…

“With the prospect of phase III data that could confirm their efficacy, checkpoint inhibitors against PD-1 and PD-L1 have shown promise, both as monotherapies and in combination with chemotherapy for patients with triple-negative breast cancer (TNBC), Sylvia Adams, MD, said during a presentation at the 16th Annual International Congress on the Future of Breast Cancer East.

” ‘We think there is definitely value for immune checkpoint blockade in triple-negative disease. When you look at the metastatic trials, while the response rates are relatively low, most of the responses are durable,’ said Adams, from the NYU Langone Medical Center. ‘For patient selection, it is important to consider the line of therapy. The earlier the better.’ ”

“Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco researchers joined by physicians from UCSF Health. The findings provide a novel predictive biomarker to identify patients who are most likely to respond well to a combination of immunotherapy drugs known as checkpoint inhibitors—and to protect those who won’t respond from potentially adverse side effects of combination treatment.

” ‘Combination immunotherapy is super-expensive and very toxic,’ said Adil Daud, MD, director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center and senior author of the new study. ‘You’re putting patients at a lot of extra risk if they don’t need it, and you can adjust for that risk by knowing in advance who can benefit.’ ”

“Improvements in OS, but not PFS, indicate that maintenance treatment with pembrolizumab may benefit a subset of patients with small cell lung cancer, and biomarkers are needed to identify individuals in whom pembrolizumab may be effective, according to findings presented at the ASCO Annual Meeting.

” ‘The standard of care for these patients – 4 to 6 cycles of platinum plus etoposide – has not changed in the United States in the last 30 years,’ Shirish Gadgeel, MD, of the Karmanos Cancer Institute in Detroit, said during a presentation. ‘Despite a high response rate with this therapy, overall outcomes for these patients are quite poor. There is a need to identify other agents that can provide benefit in these patients.’ ”

“Atezolizumab therapy produced a 22% objective response rate in first-line treatment, 19% in second-line, and 18% in third-line or higher in patients with PD-L1 expression on ≥ 5% of tumor cells (TC) or tumor-infiltrating immune cells (IC), according to Enriqueta Felip, MD, PhD, of Vall d’Hebron University Hospital in Barcelona, Spain, and colleagues. Patients with the highest levels of PD-L1 expression — TC3 or IC3 — had better objective response rates: 31% in first-line, 26% in second-line, and 27% third-line or higher.”